Abstract

The envelope (E) protein of dengue virus (DENV) is the major target of neutralizing antibodies (Abs) and vaccine development. Previous studies of human dengue-immune sera reported a significant proportion of anti-E Abs were cross-reactive to all four DENV serotypes and to one or more other flaviviruses, known as group-reactive (GR). Based on the studies of mouse anti-E monoclonal antibodies (mAbs), GR mAbs were non- or weakly neutralizing compared with type-specific mAbs; GR response was thus not regarded as important for vaccine strategy. We investigated the epitopes, binding avidity and neutralization potency of 32 human GR anti-E mAbs. In addition to fusion loop (FL) residues in E protein domain II, human GR mAbs recognized an epitope involving both FL and bc loop residues in domain II. The neutralization potency and binding avidity of GR mAbs derived from secondary DENV infection were stronger than those derived from primary infection. GR mAbs derived from primary DENV infection primarily block attachment, whereas those derived from secondary infection block DENV at post-attachment. Analysis of repertoire of anti-E mAbs dereived from patients with primary DENV infection revealed that the majority were GR, low avidity and weakly neutralizing, whereas those from secondary infection were primarily GR, high avidity and potent neutralizing. Our findings suggest the weakly neutralizing GR anti-E Abs generated from primary DENV infection become potent neutralizing against four serotypes after secondary infection. The observations that the dengue immune status of host affects the quality of cross-reactive Abs generated have implications for new strategies of DENV vaccine.